Methods of Treating Tachycardia and/or Controlling Heart Rate While Minimizing and/or Controlling Hypotension

ABSTRACT

A method of treating tachycardia while minimizing and/or controlling hypotension associated with such treatment includes administering a therapeutically effective amount of a pharmaceutical composition comprising the S-isomer of esmolol to a subject in need thereof.

CROSS-REFERENCE TO RELATED APPLICATION

The benefit under 35 U.S.C. §119(e) of U.S. provisional patentapplication Ser. No. 61/436,992 filed Jan. 27, 2011, the entiredisclosure of which is incorporated herein by reference, is herebyclaimed.

FIELD OF THE INVENTION

The invention relates to methods of treating tachycardia and/or ofcontrolling heart rate while minimizing and/or controlling hypotensionassociated therewith, the method comprising administering atherapeutically effective amount of a pharmaceutical compositioncomprising the S-isomer of esmolol.

BACKGROUND

Esmolol hydrochloride(methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionatehydrochloride) is a 50:50 racemic mixture of S- and R-isomers. Esmololhydrochloride is a fast-acting beta-blocker used for treatment ofcardiac disorders such as tachycardia, including supraventriculartachycardia, intraoperative tachycardia and postoperative tachycardia,and hypertension. Most currently available beta-blockers have relativelylong onset times. However, it is often desirable in the critical caresetting to quickly reduce rate and/or improve rhythmicity during acardiac crisis, e.g., during or shortly after a myocardial infarction.Conventional beta-blocking agents can be employed for such treatment,but their relatively long onset times can prevent a clinician fromeffectively titrating the dose quickly, e.g., when a patient is incrisis. Because of esmolol hydrochloride's relatively fast onset time,feedback is immediate and, thus, dosing can be advantageously adjustedquickly according to the patient's response.

Esmolol hydrochloride differs from conventional beta-blocking compoundsin that it contains an ester functional group which can be rapidlyhydrolyzed. Esmolol hydrochloride has a short duration in vivo due tothe presence of the ester group and is indicated for the rapid controlof ventricular rate in patients with supraventricular tachycardia (i.e.,atrial fibrillation or atrial flutter) in perioperative, postoperative,or other emergent circumstances where short term control of ventricularrate with a short-acting agent is desirable. Esmolol hydrochloride isalso indicated for the treatment of tachycardia and hypertension thatoccur during induction and tracheal intubation, during surgery, onemergence from anesthesia, and in the postoperative period. Esmololhydrochloride is typically administered by infusion.

A shortcoming of esmolol hydrochloride involves the development ofhypotension in a significant number of patients to whom it isadministered. Hypotension is listed on the packaging insert as acommonly occurring adverse event associated with esmolol treatment. SeeEsmolol Hydrochloride Injection Ready-to-use 10 mL Vials, packaginginsert (Baxter Healthcare Corporation); see also Byrd et al., JACC,3:394-9 (1984). In fact, 20-50% of patients treated with esmololhydrochloride experienced hypotension in clinical trials. See EsmololHydrochloride Injection Ready-to-use 10 mL Vials, packaging insert.Hypotension can occur at any dose but is dose-related so that esmololhydrochloride doses greater than 200 μg/kg/min are generally notrecommended. Id. Hypotension can cause oxygen deprivation in the brainand vital organs, ultimately resulting in shock. Hypotension can alsocause dizziness and fainting. Currently, hypotension is generallycontrolled in patients to whom esmolol is administered by carefullytitrating the infusion rate of the drug. It is particularly important toclosely monitor patients whose pretreatment blood pressure is low. Adesired higher infusion rate often cannot be used to lower the heartrate of a patient in stress because of concern that hypotension maydevelop and/or because of the actual development of hypotension. As aresult, esmolol hydrochloride administration often takes longer toachieve its desired therapeutic effect than it otherwise would byutilizing the desired higher infusion rate.

In view of the foregoing, it would be advantageous to retain theefficacious beta-blockade effects of esmolol hydrochloride whileminimizing the bothersome hypotension that occurs with significantfrequency in esmolol hydrochloride administration.

SUMMARY OF THE INVENTION

The present disclosure provides methods of treating cardiac conditions(e.g., tachycardia and hypertension) and/or of controlling heart rate byadministering pharmaceutical compositions comprising the S-isomer ofesmolol in order to minimize the hypotension often associated withadministration of the racemic mixture of esmolol hydrochloride.

In one aspect, the invention provides a method for treating tachycardiain a subject, the method comprising administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof, wherein the pharmaceuticalcomposition is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof, and the subject is in needof treatment for tachycardia with control of associated hypotension.

In another aspect, the invention provides a method for treatingtachycardia in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of apharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof, wherein the pharmaceuticalcomposition is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt, and wherein the therapeuticallyeffective amount is administered at a hypotension controlling amount.

In another aspect, the invention provides a method for controlling heartrate in a subject, the method comprising administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof, wherein the pharmaceuticalcomposition is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof, and the subject is in needof heart rate control with control of associated hypotension.

In another aspect, the invention provides a method for controlling heartrate in a subject in need thereof, the method comprising administeringto the subject a therapeutically effective amount of a pharmaceuticalcomposition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof, wherein the pharmaceuticalcomposition is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt, and wherein the therapeuticallyeffective amount is administered at a hypotension controlling amount.

Other features and advantages of the present invention will becomeapparent from the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an animal model for predicting the potentialhypotensive response associated with esmolol hydrochloride injection inhuman patients.

FIGS. 2A-2C illustrate the results of experiments to evaluate theeffects of administering pharmaceutical compositions comprising racemicmixtures of esmolol as compared to pharmaceutical compositionscomprising the S-isomer of esmolol. “RS” indicates the racemic mixtureof esmolol and “S” indicates the S-isomer of esmolol.

FIGS. 3A-3C illustrate the results of experiments to evaluate theeffects of administering pharmaceutical compositions comprising racemicmixtures of esmolol as compared to pharmaceutical compositionscomprising the S-isomer of esmolol.

FIGS. 4A-4C illustrate the results of experiments to evaluate theeffects of administering pharmaceutical compositions comprising racemicmixtures of esmolol as compared to pharmaceutical compositionscomprising the S-isomer of esmolol.

FIGS. 5A-5C illustrate the results of experiments to evaluate theeffects of administering pharmaceutical compositions comprising racemicmixtures of esmolol as compared to pharmaceutical compositionscomprising the S-isomer of esmolol.

FIGS. 6A-6C illustrate the results of experiments to evaluate whetherthe attenuated hypotension observed with the S-isomer formulations ofFIGS. 2-5 reduced the efficacy (i.e., ability to controlisoproterenol-induced tachycardia) of the S-isomer formulations ascompared with the racemic formulations.

FIGS. 7A and 7B illustrate the results of experiments to evaluate theeffects of administering pharmaceutical compositions comprising racemicmixtures of esmolol as compared to pharmaceutical compositionscomprising the R-isomer of esmolol and pharmaceutical compositionscomprising the S-isomer of esmolol.

FIGS. 8A and 8B illustrate the results of experiments to evaluate theeffects of administering pharmaceutical compositions comprising racemicmixtures of esmolol as compared to pharmaceutical compositionscomprising the R-isomer of esmolol and pharmaceutical compositionscomprising the S-isomer of esmolol.

FIGS. 9A and 9B illustrate the results of experiments to evaluate theeffects of administering pharmaceutical compositions comprising racemicmixtures of esmolol as compared to pharmaceutical compositionscomprising the R-isomer of esmolol and pharmaceutical compositionscomprising the S-isomer of esmolol.

FIG. 10 illustrates the results of experiments comparing the hypotensiveresponse after administering pharmaceutical compositions comprisingracemic mixtures of esmolol as compared to pharmaceutical compositionscomprising the R-isomer of esmolol and pharmaceutical compositionscomprising the S-isomer of esmolol. The results displayed are theaverages of the percent change in mean arterial pressure from a restingbaseline state, just prior to beginning a particular infusion to the endof a particular infusion.

FIG. 11 illustrates the results of experiments comparing the change inmean arterial pressure when immediately transitioning fromadministration of one pharmaceutical composition to another. The resultsdisplayed are the averages of the percent change in mean arterialpressure from the end of the first infusion to the end of the secondinfusion.

FIGS. 12A and 12B illustrate the results of experiments evaluating theeffects of administering pharmaceutical compositions comprising racemicmixtures of esmolol following isoproterenol challenge as compared topharmaceutical compositions comprising the S-isomer of esmolol followingisoproterenol challenge.

FIG. 13 illustrates the effects of administering pharmaceuticalcompositions comprising racemic mixtures of esmolol on systolic bloodpressure from the aforementioned experiments in dogs as compared withhumans.

DETAILED DESCRIPTION OF THE INVENTION

The invention disclosed herein provides improved methods of treatingcardiac conditions (e.g., tachycardia and hypertension) and/or ofcontrolling heart rate while concurrently minimizing and/or controllinghypotension often associated with the administration of pharmaceuticalcompositions comprising the racemic mixture of esmolol by administeringpharmaceutical compositions comprising the S-isomer of esmolol. Thepresent inventors unexpectedly and surprisingly found that administeringa therapeutically effective amount of a pharmaceutical compositioncomprising the S-isomer of esmolol, and preferably the S-isomer ofesmolol hydrochloride, demonstrates substantially similar heart ratecontrol and causes significantly less hypotension than administration ofthe racemic mixture, particularly relative to administration of anamount of the racemic mixture that corresponds to an equitherapeuticamount of the S-isomer of esmolol. As a result of the reduced tendencyto induce hypotension, therapeutic drug concentrations or infusion ratesof the S-isomer of esmolol may be administered more safely than with theracemic mixture. Moreover, patients susceptible to hypotension with theesmolol racemic mixture may be treated with the S-isomer of esmololwhile minimizing and/or controlling hypotension. Therefore, the presentinvention advantageously affords a significantly higher degree of safetyby beneficially minimizing and/or controlling the development ofhypotension in patients who receive compositions comprising the S-isomerof esmolol, while also advantageously allowing higher therapeutic dosesof the S-isomer of esmolol to be utilized than in prior art methods inwhich compositions comprising the racemic mixture were administered.Thus, the invention allows the clinician to advantageously attend to thetachycardia and/or hypertension experienced by the patient or to moreeasily control the heart rate of the patient while minimizing the needfor careful titration of the drug and for closely monitoring patientswhose pretreatment blood pressure is low.

In one aspect, the invention provides a method for treating tachycardiain a subject, the method comprising administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof, wherein the pharmaceuticalcomposition is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof, and the subject is in needof treatment for tachycardia with control of associated hypotension.

In another aspect, the invention provides a method for treatingtachycardia in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of apharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof, wherein the pharmaceuticalcomposition is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt, and wherein the therapeuticallyeffective amount is administered at a hypotension controlling amount.

In an additional aspect, the invention provides a method for controllingheart rate in a subject, the method comprising administering to thesubject a therapeutically effective amount of a pharmaceuticalcomposition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof, wherein the pharmaceuticalcomposition is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof, and the subject is in needof heart rate control with control of associated hypotension.

In yet another aspect, the invention provides a method for controllingheart rate in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of apharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof, wherein the pharmaceuticalcomposition is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt, and wherein the therapeuticallyeffective amount is administered at a hypotension controlling amount.

The cardiac conditions and/or disorders which can be treated by themethods of the invention include any cardiac condition known to benefitfrom treatment with esmolol. Such cardiac conditions include, but arenot limited to, tachycardia (e.g., supraventricular tachycardia,intraoperative and postoperative tachycardia) and hypertension (e.g.,intraoperative and postoperative hypertension). Moreover, the methods ofthe invention can also be used to control heart rate in a patient, whenclinically desirable, whether or not the subject has one of theaforementioned cardiac conditions.

As used herein, the terms “pharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof,” and “pharmaceuticalcomposition comprising the S-isomer of esmolol” refer to pharmaceuticalcompositions which are substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof. The term “substantially freeof (R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate”refers to compositions that contain less than 10% by weight, less than5% by weight, less than 3% by weight, less than 2% by weight, less than1% by weight, and/or less than 0.5% by weight(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof based on the total amount ofmethyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof in the composition. Preferably,compositions “substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate”contain 5 wt. % or less of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof based on the total amount ofmethyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof in the composition, e.g., lessthan 3 wt. %, less than 2 wt. %, less than 1 wt. %, and/or less than 0.5wt. %. The total esmolol content can be determined using a standard HPLCcolumn or similar analytical method known in the art. The respectiverelative contents of the S-isomer of esmolol and the R-isomer of esmololin a given composition can be determined using a chiral HPLC method orsimilar analytical method known in the art. See, e.g., Tang et al., J.Biochem. Biophys. Methods, 59:159-166 (2004).

In one aspect, a “therapeutically effective amount” refers to an amountof a pharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof which is sufficient tocontrol tachycardia and/or hypertension. Thus, an amount sufficient tocontrol tachycardia includes but is not limited to an amount sufficientto alleviate and/or ameliorate tachycardia and/or hypertension.

In another aspect, a “therapeutically effective amount” refers to anamount of a pharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof which is sufficient tocontrol heart rate. Thus, an amount sufficient to control heart rateincludes but is not limited to an amount sufficient to control and/orreduce an elevated heart rate.

In all aspects of the disclosure, the therapeutically effective amountcan be a hypotension controlling amount as defined below.

The term “hypotension controlling amount” refers to an amount of apharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof that provides the therapeuticbenefits of a composition comprising the racemic mixture of esmolol(e.g., control of tachycardia and/or hypertension and/or control ofheart rate) while minimizing the hypotension often associated withadministration of the racemic mixture of esmolol. Therefore, ahypotension controlling amount can be any therapeutically effectiveamount which does not cause hypotension in a subject, particularlyrelative to administration of the racemic mixture which has been shownto induce hypotension in 20-50% of humans. See Esmolol HydrochlorideInjection Ready-to-use 10 mL Vials, packaging insert. Thus, in variousaspects, a hypotension controlling amount is greater than or equal to37.5 nmol/kg/min of the S-isomer of esmolol (i.e., about 12.5 μg/kg/minof the S-isomer of esmolol hydrochloride) which corresponds to about 25μg/kg/min of the racemic mixture of esmolol hydrochloride, greater thanor equal to 75 nmol/kg/min of the S-isomer of esmolol (e.g., about 25μg/kg/min of the S-isomer of esmolol hydrochloride) which corresponds toabout 50 μg/kg/min of the racemic mixture of esmolol hydrochloride,and/or greater than or equal to 0.15 μmol/kg/min of the S-isomer ofesmolol (e.g., about 50 μg/kg/min of the S-isomer of esmololhydrochloride) which corresponds to about 100 μg/kg/min of the racemicmixture of esmolol hydrochloride. Moreover, because doses of 200μg/kg/min of racemic esmolol hydrochloride are generally not recommended(see Esmolol Hydrochloride packaging insert), in one aspect, ahypotension controlling amount of a pharmaceutical compositioncomprising the S-isomer of esmolol or a pharmaceutically acceptable saltthereof can refer to a dose of the S-isomer of esmolol which is greaterthan or equal to 0.3 mmol/kg/min (e.g., about 100 μg/kg/min of theS-isomer of esmolol hydrochloride) which corresponds to about 200μg/kg/min of the racemic mixture of esmolol hydrochloride. Otherexemplary hypotension controlling amounts of a pharmaceuticalcomposition comprising the S-isomer of esmolol in accordance with thisaspect include but are not limited to greater than or equal to 0.45μmol/kg/min of the S-isomer of esmolol (e.g., about 150 μg/kg/min of theS-isomer of esmolol hydrochloride) which corresponds to about 300μg/kg/min of the racemic mixture of esmolol hydrochloride, greater thanor equal to 0.6 μmol/kg/min of the S-isomer of esmolol (e.g., about 200μg/kg/min of the S-isomer of esmolol hydrochloride) which corresponds toabout 400 μg/kg/min of the racemic mixture of esmolol hydrochloride,greater than or equal to 0.75 μmol/kg/min of the S-isomer of esmolol(e.g., about 250 μg/kg/min of the S-isomer of esmolol hydrochloride)which corresponds to about 500 μg/kg/min of the racemic mixture ofesmolol hydrochloride, greater than or equal to 0.90 μmol/kg/min of theS-isomer of esmolol (e.g., about 300 μg/kg/min of the S-isomer ofesmolol hydrochloride) which corresponds to about 600 μg/kg/min of theracemic mixture of esmolol hydrochloride, greater than or equal to 1.05μmol/kg/min of the S-isomer of esmolol (e.g., about 350 μg/kg/min of theS-isomer of esmolol hydrochloride) which corresponds to about 700μg/kg/min of the racemic mixture of esmolol hydrochloride, greater thanor equal to 1.125 mmol/kg/min of the S-isomer of esmolol (e.g., about375 μg/kg/min of the S-isomer of esmolol hydrochloride) whichcorresponds to about 750 μg/kg/min of the racemic mixture of esmololhydrochloride, greater than or equal to 1.20 μmol/kg/min of the S-isomerof esmolol (e.g., about 400 μg/kg/min of the S-isomer of esmololhydrochloride) which corresponds to about 800 μg/kg/min of the racemicmixture of esmolol hydrochloride, greater than or equal to 1.35μmol/kg/min of the S-isomer of esmolol (e.g., about 450 μg/kg/min of theS-isomer of esmolol hydrochloride) which corresponds to about 900μg/kg/min of the racemic mixture of esmolol hydrochloride, greater thanor equal to 1.5 μmol/kg/min of the S-isomer of esmolol (e.g., about 500μg/kg/min of the S-isomer of esmolol hydrochloride) which corresponds toabout 1000 μg/kg/min of the racemic mixture of esmolol hydrochloride,greater than or equal to 1.8 μmol/kg/min of the S-isomer of esmolol(e.g., about 600 μg/kg/min of the S-isomer of esmolol hydrochloride)which corresponds to about 1200 μg/kg/min of the racemic mixture ofesmolol hydrochloride, greater than or equal to 2.1 μmol/kg/min of theS-isomer of esmolol (e.g., about 700 μg/kg/min of the S-isomer ofesmolol hydrochloride) which corresponds to about 1400 μg/kg/min of theracemic mixture of esmolol hydrochloride, greater than or equal to 2.4μmol/kg/min of the S-isomer of esmolol (e.g., about 800 μg/kg/min of apharmaceutical composition comprising the S-isomer of esmololhydrochloride) which corresponds to about 1600 μg/kg/min of the racemicmixture of esmolol hydrochloride, greater than or equal to 2.7μmol/kg/min of the S-isomer of esmolol (e.g., about 900 μg/kg/min of theS-isomer of esmolol hydrochloride) which corresponds to about 1800μg/kg/min of the racemic mixture of esmolol hydrochloride, and/orgreater than or equal to 3.0 μmol/kg/min of the S-isomer of esmolol(e.g., about 1000 μg/kg/min of the S-isomer of esmolol hydrochloride)which corresponds to about 2000 μg/kg/min of the racemic mixture ofesmolol hydrochloride. For example, a hypotension controlling amount ofa pharmaceutical composition comprising the S-isomer or apharmaceutically acceptable salt can be administered in an amountbetween 37.5 nmol/kg/min and 3.0 μmol/kg/min, between 37.5 nmol/kg/minand 1.5 μmol/kg/min, between 37.5 nmol/kg/min and 0.75 μmol/kg/min,between 75 nmol/kg/min and 3.0 μmol/kg/min, between 75 nmol/kg/min and1.5 μmol/kg/min, between 75 nmol/kg/min and 0.75 μmol/kg/min, between0.15 μmol/kg/min and 3.0 μmol/kg/min, between 0.15 mmol/kg/min and 1.5μmol/kg/min, between 0.15 μmol/kg/min and 0.75 μmol/kg/min, between 0.3μmol/kg/min and 1.5 μmol/kg/min, between 0.45 μmol/kg/min and 1.5mmol/kg/min, between 0.6 μmol/kg/min and 1.5 μmol/kg/min, between 0.75μmol/kg/min and 1.5 μmol/kg/min, between 0.90 μmol/kg/min and 1.5μmol/kg/min, between 1.05 mmol/kg/min and 1.5 μmol/kg/min, and/orbetween 1.20 μmol/kg/min and 1.5 μmol/kg/min.

The term “pharmaceutically acceptable salt” refers to those salts whichretain the biological efficacy and properties of the esmolol, and whichare not biologically or otherwise undesirable. Such salts can be formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like, preferablyhydrochloric acid, and organic acids such as acetic acid, propionicacid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonicacid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and thelike. In all disclosed embodiments, the pharmaceutically acceptable saltof (S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionatecan be(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionatehydrochloride.

In one aspect, the term a “subject in need thereof” (i.e., in need oftachycardia and/or hypertension treatment) is defined as an individualwho would benefit from administration of a beta blocker to controltachycardia and/or hypertension.

In another aspect, the term a “subject in need thereof” (i.e., in needof heart rate control) is defined as an individual who would benefitfrom administration of a beta blocker to control an elevated heart rate.

The term “in need of treatment for tachycardia with control ofassociated hypotension” refers to an individual who would benefit fromadministration of a beta blocker to control tachycardia and/orhypertension and is susceptible to the development of associatedhypotension at the administered dose.

The term “in need of heart rate control with control of associatedhypotension” refers to an individual having an elevated heart rate whowould benefit from administration of a beta blocker and is susceptibleto the development of associated hypotension at the administered dose.

As used herein, the term “tachycardia” refers to an abnormally fastheart beat, typically for humans age 15 or older, a heart rate greaterthan 100 beats per minute at rest. “Supraventricular tachycardia” refersto such an abnormally fast heart beat originating in the atria.

As used herein, the term “hypotension” refers to abnormally low bloodpressure. As appreciated by those of skill in the art, blood pressurecharacterized as “hypotensive” may vary from individual to individual.Hypotension, however, is generally defined as systolic pressure lessthan 90 mmHg and/or diastolic pressure less than 50 mmHg.

As used herein, the term “hypertension” refers to abnormally high bloodpressure. As appreciated by those of skill in the art, blood pressurecharacterized as “hypertensive” may vary from individual to individual.Hypertension, however, is generally defined as systolic pressure greaterthan 140 mmHg and/or diastolic pressure greater than 90 mmHg.

As used herein, the term “elevated heart rate” refers to a heart ratethat is more than 20 beats per minute higher than an individual's normalresting pulse, more typically more than 25 beats per minute higher thanthe individual's normal resting pulse, and/or more than 30 beats perminute higher than the individual's normal resting pulse. Such elevatedheart rates may not be tachycardias as defined herein, but tachycardiaare also encompassed by the foregoing definition of elevated heart rate.

While beta blockers are often manufactured and commercialized as the RSracemic mixture, the S-isomer is generally responsible for all of thebeta blocking activity. See Mehvar and Brocks, J. Pharm. Pharmaceut.Sci., 4(2):185-200 (2001). Consistent with the foregoing, the S-isomerof esmolol has been demonstrated to be about twice as potent as abeta-adrenergic-blocking agent than an equivalent amount of the racemicmixture. See International Patent Publication No. WO 88/01614. Thus, asused herein, the terms “equitherapeutic amount” or “therapeuticallyequivalent amount” refer to an amount of(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof that provides the sametherapeutic beta-blockade benefit as a given amount of the racemicmixture ofmethyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionatehydrochloride. In general, the equitherapeutic amount of(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof is one-half the amount of theracemic mixture ofmethyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionatehydrochloride. In other words, if the racemic mixture is administered ata rate of 300 μg/kg/min, the equitherapeutic amount of the S-isomer ofesmolol is 150 μg/kg/min.

The pharmaceutical composition of the present invention is suitable forparenteral administration to a patient. Suitable routes for parenteraladministration include intravenous, subcutaneous, intradermal,intramuscular, intraarticular, and intrathecal. For example, thepharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof may be administered in the formof a bolus injection, intravenous infusion, or combination bolusinjection/intravenous infusion. The ready-to-use formulation of theinvention is preferably administered by intravenous infusion.

The pharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof typically takes the form of asterile, ready-to-use composition that is suitable for infusion. Theready-to-use presentation avoids the inconvenience of diluting aconcentrated small volume parenteral formulation into infusion diluentsprior to infusion, as well as eliminates the risk of microbiologicalcontamination during handling and dilution and any potential calculationor dilution error. As used herein, a “ready-to-use” formulation orcomposition is defined as a pharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof that does not need dilutionbefore administration to the patient. Similarly, “suitable for parentalinfusion” refers to formulations or compositions wherein the pH andosmolarity have been adjusted to physiological or near-physiologicallevels appropriate for administration to the patient by infusion. Suchformulations or compositions can be essentially free from propyleneglycol and ethanol. In alternative embodiments, the pharmaceuticalcomposition comprising the S-isomer of esmolol can also take the form ofa concentrated formulation which must be diluted prior toadministration.

When treating tachycardias, the administered dose of the pharmaceuticalcomposition comprising the S-isomer of esmolol hydrochloride istypically titrated using the ventricular rate as a guide. Generally, theadministered dose of the S-isomer of esmolol hydrochloride is between12.5 μg/kg/minute and 1000 μg/kg/minute, between 12.5 μg/kg/minute and500 μg/kg/minute, between 12.5 μg/kg/minute and 400 μg/kg/minute,between 12.5 μg/kg/minute and 300 μg/kg/minute, between 12.5μg/kg/minute and 200 μg/kg/minute, and/or between 12.5 μg/kg/minute and100 μg/kg/minute. For example, a representative dosing protocol fortreating supraventricular tachycardia may include an initial loadingdose of 250 μg S-isomer esmolol hydrochloride/kg body weight (μg/kg)infused over a minute duration followed by a maintenance infusion of 25μg/kg/minute S-isomer of esmolol hydrochloride for 4 minutes to obtain aguide with respect to the responsiveness of ventricular rate. A lowerinitial maintenance dose of S-isomer of esmolol hydrochloride such as,for example, 12.5 μg/kg/minute, or a higher initial maintenance dose ofS-isomer of esmolol hydrochloride such as, for example, 37.5μg/kg/minute, 50 μg/kg/minute, 62.5 μg/kg/minute, 75 μg/kg/minute, 87.5μg/kg/minute, or even 100 μg/kg/minute may be used. In the dosecalculations for the compositions comprising the S-isomer of esmololaccording to the invention, it is assumed that the administered esmololcomprises 100% S-isomer. In some instances, after the 4 minutes ofinitial maintenance infusion and depending on whether the desiredventricular response has been achieved, the loading dose of 250 μg/kgS-isomer of esmolol hydrochloride infused over a 1 minute period isrepeated, followed by an additional maintenance infusion which may becontinued at 25 μg/kg/minute or increased step-wise to 50 μg/kg/minutefor 4 more minutes. If an adequate therapeutic effect is not observed atthis point, a third loading dose of 250 μg/kg S-isomer of esmololhydrochloride may be repeated over 1 minute and followed with anadditional maintenance infusion of S-isomer of esmolol hydrochloridewhich may be continued at the original 25 μg/kg/minute or increased toeither 50 μg/kg/minute or 75 μg/kg/minute for 4 minutes. Maintenanceinfusions may then be continued for up to 48 hours at up to 100μg/kg/minute to achieve the desired therapeutic effect. After achievingan adequate control of the heart rate and a stable clinical status inpatients with supraventricular tachycardia, transition to alternativeantiarrhythmic agents such as propranolol, digoxin, or verapamil, may beaccomplished. As will be appreciated by those of ordinary skill in theart, because the S-isomer of esmolol minimizes the hypotension oftenassociated with administration of the racemic mixture of esmolol, theloading dose can be higher than 250 μg/kg S-isomer esmolol hydrochlorideif higher doses are indicated because of the need to rapidly controlsevere tachycardias. Thus, the loading dose of the S-isomer of esmololhydrochloride can be greater than or equal to 300 μg/kg/min, greaterthan or equal to 350 μg/kg/min, greater than or equal to 400 μg/kg/min,greater than or equal to 450 μg/kg/min, greater than or equal to 500μg/kg/min, greater than or equal to 550 μg/kg/min, greater than or equalto 600 μg/kg/min, greater than or equal to 650 μg/kg/min, greater thanor equal to 700 μg/kg/min, greater than or equal to 750 μg/kg/min,greater than or equal to 800 μg/kg/min, greater than or equal to 850μg/kg/min, greater than or equal to 900 μg/kg/min, greater than or equalto 950 μg/kg/min, and/or greater than or equal to 1000 μg/kg/min. If apharmaceutically acceptable salt of S-esmolol other than thehydrochloride salt is administered, the molar equivalent to the aboveranges can be administered.

When immediate response/control is desired in a clinical situation, forexample, when treating acute intraoperative tachycardia and/or acuteintraoperative hypertension, a representative dosing protocol includesadministering a bolus dose of approximately 500 μg/kg S-isomer ofesmolol hydrochloride over 30 seconds, followed by infusion of 75μg/kg/min S-isomer of esmolol hydrochloride, if necessary. The infusionrate can be adjusted up to 150 μg/kg/min S-isomer of esmololhydrochloride to maintain (or achieve) to reach the desired heart rateand/or blood pressure, as necessary. Again, if a pharmaceuticallyacceptable salt of S-esmolol other than the hydrochloride salt isadministered, the molar equivalent to the above ranges can beadministered.

On the other hand, when gradual response/control is acceptable, forexample, when treating postoperative tachycardia and/or postoperativehypertension, the representative dosing protocol for treatingsupraventricular tachycardia may be used. Additionally, therepresentative dosing protocol for treating supraventricular tachycardiamay also be used by clinicians to successfully control the heart ratesof patients having elevated heart rates (i.e., elevated relative to thepatient's normal resting pulse, as previously described).

It will be appreciated that the treatment methods of the invention areuseful in the fields of human medicine and veterinary medicine. Thus,the subject or individual to be treated may be an animal, for example, amammal, preferably human.

Containers suitable for packaging the pharmaceutical compositioncomprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof according to the presentinvention include numerous sealed containers known in the art including,but not limited to, vials, syringes, bags, bottles, and ampulpresentations. Containers may be fabricated from glass or from polymericmaterials. Ready-to-use formulations are typically packaged in vials,syringes, bags and bottles, while concentrated formulations aretypically packaged in ampuls.

Pharmaceutical compositions according to the present invention can beprepared into small volume parenteral (SVP) and large volume parenteral(LVP) dosage forms. The dosage forms can be packaged in any suitablecontainer. Suitable containers include, for example, glass vials,polymeric vials, ampuls, syringes, and bags with sizes ranging from 1 mLto 500 mL. SVP solutions are typically filled into ampules and vials in1-100 mL presentations. In addition, syringes can be used as thecontainer for a SVP, which are sold as “pre-filled syringes.” The LVPpresentations can be contained in bags or bottles. A preferredpresentation for ready-to-use LVP is a polymeric bag.

Polymeric containers, such as polymeric bags, are preferably flexibleand can contain or be free of polyvinylchloride (PVC). Preferredcontainers are free of PVC, such as those disclosed in U.S. Pat. Nos.5,849,843 and 5,998,019. Polymeric containers can further be providedwith a moisture barrier as a secondary packaging system to prevent theloss of water during storage and to further ensure the stability of theformulation. A preferred moisture barrier is an aluminum overpouch.

The pH of the pharmaceutical composition can affect the stability of the(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof. The pH should be between 3.5and 6.5, preferably between 4.5 and 5.5, more preferably about 5.0. ThepH can be adjusted as known in the art, for example, by addition ofsodium hydroxide or hydrochloric acid.

The S-isomer of esmolol or pharmaceutically acceptable salt thereof istypically present in the pharmaceutical composition according to theinvention in a concentration ranging from 0.3 mM-3.0 M (i.e.,corresponding to about 0.1-1000 mg/mL of S-isomer esmololhydrochloride). Ready-to-use formulations generally contain 0.3 mM-300mM (i.e., corresponding to about 0.1-100 mg/mL S-isomer esmololhydrochloride), 3-150 mM (i.e., corresponding to about 1-50 mg/mLS-isomer esmolol hydrochloride), and/or 3-75 mM (i.e., corresponding toabout 1-25 mg/mL S-isomer esmolol hydrochloride) of S-isomer esmolol orpharmaceutically acceptable salt thereof. Concentrated formulations maycontain 300-1500 mM (i.e., corresponding to about 100-500 mg/mL S-isomeresmolol hydrochloride), for example, 300-750 mM (i.e., corresponding toabout 100-250 mg/mL S-isomer esmolol hydrochloride) of S-isomer esmololor pharmaceutically acceptable salt thereof.

Suitable buffering agents are known in the art, and are typicallypresent in the pharmaceutical compositions according to the invention ina concentration ranging from 0.01-2 M. Ready-to-use formulationstypically have buffering agent concentrations of 0.01-0.5 M, forexample, 0.02-0.1 M. Concentrated formulations typically have bufferingagent concentrations of 0.5-2 M. Exemplary buffering agents include, butare not limited to, acetate, glutamate, citrate, tartrate, benzoate,lactate, gluconate, phosphate and glycine. A preferred buffering agentcomprises a combination of sodium acetate and glacial acetic acid.

The pharmaceutical compositions of the invention typically are aqueous.Such aqueous pharmaceutical compositions may further comprise apharmaceutically acceptable co-solvent to assist in solubilization ofthe S-isomer of esmolol or pharmaceutically acceptable salt thereof.Alternatively, the pharmaceutical compositions of the invention may besolvent-based comprising one or more pharmaceutically acceptablesolvents. Examples of pharmaceutically acceptable solvents (andco-solvents) include but are not limited to ethanol, isopropanol, ethylacetate, acetic acid, and ethanolamine.

Suitable osmotic-adjusting agents are known in the art, and aretypically present in the pharmaceutical compositions according to theinvention in an amount ranging from 1-500 mg/mL. Exemplaryosmotic-adjusting agents include, but are not limited to, sodiumchloride, dextrose, sodium bicarbonate, calcium chloride, potassiumchloride, sodium lactate, Ringer's solution and lactated Ringer'ssolution. Preferred osmotic adjusting agents include sodium chlorideand/or dextrose. Ready-to-use formulations may contain 1-100 mg/mLosmotic-adjusting agent, for example, 3-60 mg/mL sodium chloride or 3-10mg/mL sodium chloride. Concentrated formulations intended for dilutionmay contain 1-500 mg/mL or 50-500 mg/mL osmotic-adjusting agent.

Procedures for filling pharmaceutical compositions of the presentinvention in containers, and their subsequent processing are known inthe art. These procedures are conventionally used to produce sterilepharmaceutical drug products often required for health care. Suchprocessing techniques preferably use a sterilization process to destroyor eliminate any microorganisms that may be present in thepharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof following preparation and/orpackaging of the pharmaceutical compositions. For example, terminalsterilization can be used to destroy all viable microorganisms withinthe final, sealed package containing the pharmaceutical composition. Anautoclave is commonly used to accomplish terminal heat-sterilization ofdrug products in their final packaging.

Typical autoclave cycles in the pharmaceutical industry to achieveterminal sterilization of the final product are 121° C. for 15 minutes.The composition comprising the S-isomer of esmolol of the presentinvention can be autoclaved at a temperature ranging from 115° C. to130° C. for a period of time ranging from 5 to 40 minutes withoutcausing substantial degradation of the(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof. Autoclaving is preferablycarried out in the temperature range of 119° C. to 122° C. for a periodof time ranging from 10 to 36 minutes.

Alternatively, sterile pharmaceutical compositions according to thepresent invention may be prepared using aseptic processing techniques.Aseptic filling is ordinarily used to prepare drug products that willnot withstand heat sterilization, but in which all of the ingredientsare sterile. Sterility is maintained by using sterile materials and acontrolled working environment. All containers and apparatus aresterilized, preferably by heat sterilization, prior to filling. Thecontainer (e.g., vial, ampul, bag, bottle, or syringe) are then filledunder aseptic conditions.

As explained above, the methods of the invention are particularlypertinent to the treatment of patients in need of beta blockade and whoare susceptible to hypotension. Thus, patients prone to hypotension areparticularly suited for treatment by the disclosed methods. Byadministering a composition comprising S-esmolol in accordance with theinvention to patients susceptible to hypotension, the patients receivethe beta-blocking benefits of esmolol while minimizing the hypotensionthat often occurs following administration of the racemic mixture ofesmolol. Cardiac conditions that benefit from treatment with a betablocker include, but are not limited to, tachycardia (e.g.,supraventricular tachycardia, intraoperative and postoperativetachycardia) and hypertension (e.g., intraoperative and postoperativehypertension). Moreover, the methods of the invention can also be usedto control an elevated heart rate in a patient, when clinicallydesirable, whether or not the patient has one of the aforementionedcardiac conditions. Conditions that render subjects in need ofbeta-blockade susceptible to hypotension are particularly pertinent forthe methods of the invention are described below.

In various embodiments, subjects treated according to the methods of theinvention are in need of beta blockade and are susceptible tohypotension. Subjects are susceptible to hypotension for a variety ofreasons including, but not limited to, situations when administration ofa relatively high therapeutic dose of racemic esmolol hydrochloride isindicated (e.g., an infusion rate of a pharmaceutical compositioncomprising racemic esmolol hydrochloride of greater than or equal to 200μg/kg/min, greater than or equal to 250 μg/kg/min of the racemicmixture, greater than or equal to 300 μg/kg/min of the racemic mixture,greater than or equal to 400 μg/kg/min of the racemic mixture, greaterthan or equal to 500 μg/kg/min, greater than or equal to 750 μg/kg/min,and/or greater than or equal to 1000 μg/kg/min, for example, an amountbetween 200 μg/kg/min and 1000 μg/kg/min of racemic esmololhydrochloride), advanced age, genetic abnormalities, hypovolemia, anddiabetic and pre-diabetic conditions. Because preferred doses of racemicesmolol for treating tachycardias are well known in the art, appropriatedoses of compositions comprising the S-isomer of esmolol may be easilydetermined by standard methods.

For example, when relatively high infusion rates of the racemic mixtureof esmolol are indicated and administered to humans (e.g., amountsgreater than or equal to 200 μg/kg/min of the racemic mixture, greaterthan or equal to 250 μg/kg/min of the racemic mixture, greater than orequal to 300 μg/kg/min of the racemic mixture, greater than or equal to400 μg/kg/min of the racemic mixture, greater than or equal to 500μg/kg/min of the racemic mixture, greater than or equal to 750 μg/kg/minof the racemic mixture, and/or greater than or equal to 1000 μg/kg/minof the racemic mixture), such subjects are particularly susceptible tohypotension. Thus, in various embodiments, the subjects treatedaccording to the methods of the invention can receive relatively hightherapeutic doses of the S-isomer of esmolol hydrochloride, e.g., aninfusion rate of the S-isomer of esmolol or pharmaceutically acceptablesalt of greater than or equal to 0.3 μmol/kg/min (e.g., 100 μg/kg/minS-isomer esmolol hydrochloride), greater than or equal to 0.45μmol/kg/min (e.g., 150 μg/kg/min S-isomer esmolol hydrochloride),greater than or equal to 0.75 μmol/kg/min (e.g., 250 μg/kg/min S-isomeresmolol hydrochloride), greater than or equal to 1.125 mmol/kg/min(e.g., 375 μg/kg/min S-isomer esmolol hydrochloride), and/or greaterthan or equal to 1.5 μmol/kg/min (e.g., 500 μg/kg/min S-isomer esmololhydrochloride), for example, an amount between 0.3 μmol/kg/min and 1.5μmol/kg/min, to achieve greater and more immediate therapeutic effectwhile minimizing the hypotensive effects often associated withadministration of the corresponding doses (here, corresponding infusionrates) of the racemic mixture of esmolol hydrochloride, as compared tothe equitherapeutic amount of the S-isomer esmolol hydrochloride.

Additionally, patients of advanced age are known to be susceptible tohypotension. Thus, in various embodiments, the patients in need oftreatment are in need of beta blockade and are age 65 or older.

Patients suffering from orthostatic hypotension are also susceptible todeveloping hypotension as a result of receiving esmolol. Orthostatichypotension is defined as a condition in which a patient moves from agenerally supine position to a generally upright position andexperiences an accompanying drop in blood pressure. Therefore, in otherembodiments, the patient in need of treatment by the methods of theinvention is in need of beta blockade and suffers from, or is prone to,episodes of orthostatic hypotension. Moreover, episodes of orthostatichypotension occur more frequently in adults age 65 and older. SeeBenvenuto and Krakoff, Am J Hypertens (2010). Thus, in some embodimentsthe patient in need of treatment by the methods of the invention is age65 or older and has a history of orthostatic hypotensive episodes.

Patients with diabetes have a higher risk of orthostatic hypotension andthus are susceptible to developing hypotension. See Wu et al., DiabetesCare, 32:1, 69-74 (2009). In some embodiments, the patient in need oftreatment by the methods of the invention suffers from type I diabetes,type II diabetes, or are considered to have “pre-diabetes,” a conditionin which an individual's blood glucose levels are elevated, but not asmuch as individuals having diabetes. Glucose levels are generallydetermined by using a Fasting Plasma Glucose Test (FPG) or an OralGlucose Tolerance Test (OGTT), but other tests may also be used. Withthe FPG test, a fasting blood glucose level between 100 and 125milligrams per deciliter (mg/dL) is indicative of pre-diabetes, and afasting blood glucose level of 126 mg/dL or higher is indicative ofdiabetes. With the OGTT test, an individual's blood glucose level ismeasured two hours after drinking a glucose-rich beverage. A two-hourblood glucose level between 140 and 199 mg/dL is indicative ofpre-diabetes, and a two-hour blood glucose level at 200 mg/dL or higheris indicative of diabetes.

Patients suffering from familial orthostatic hypotensive disorder arealso susceptible to developing hypotension as a result of receivingesmolol. Familial orthostatic hypotensive disorder is characterized bylight-headedness on standing, which may worsen to syncope, palpitations,and blue-purple ankle discoloration, and is accompanied by a markeddecrease in systolic blood pressure, an increase in diastolic pressure,and tachycardia, all of which resolve when supine. See DeStefano et al.,AJHG, 63:5, 1425-1430 (1998). In some embodiments, the patient in needof treatment by the methods of the invention suffers from familialorthostatic hypotensive disorder.

Several genetic abnormalities including, but not limited to, aldosteronedeficiency (e.g., Ulick syndrome or Visser syndrome), Algrove syndrome,tetrahyrdobiopterin deficiency, aromatic L-amino acid decarboxylasedeficiency, monoamine oxidase deficiency, dopamine-β-hydroxylasedeficiency, Biaggioni syndrome, Menkes syndrome (trichopolydystrophy),familial dysautonomia (Riley-Day syndrome), hereditary sensory and motorneuropathies, familial amyloidosis (Andrade syndrome), familialolivopontocerebellar atrophy, mitral valve prolapsed syndrome,hereditary mast cell activation disorder, and Bartter syndrome have beenshown to be associated with susceptibility to developing hypotension.See Robertson, Curr Opin Nephrol Hypertens, 3(1):13-24 (1994). Thus, invarious embodiments, the patient in need of treatment by the methods ofthe invention suffers from one or more disorders selected from the groupconsisting of aldosterone deficiency (e.g., Ulick syndrome or Vissersyndrome), Algrove syndrome, tetrahyrdobiopterin deficiency, aromaticL-amino acid decarboxylase deficiency, monoamine oxidase deficiency,dopamine-β-hydroxylase deficiency, Biaggioni syndrome, Menkes syndrome(trichopolydystrophy), familial dysautonomia (Riley-Day syndrome),hereditary sensory and motor neuropathies, familial amyloidosis (Andradesyndrome), familial olivopontocerebellar atrophy, mitral valve prolapsedsyndrome, hereditary mast cell activation disorder, and Barttersyndrome.

Further, hypotension is a common occurrence after induction of generalanesthesia. See Reich et al., Anesth Analg, 101:3, 622-628 (2005). Thus,in some embodiments, the patient in need of treatment by the methods ofthe invention is in need of beta blockade and is either undergoing aprocedure under general anesthesia, or was administered generalanesthesia within the last 36 hours. Similarly, hypotension is one ofthe most frequent side effects of spinal anesthesia. See Hartmann etal., Anesthesia & Analgesia, 94:6, 1521-1529 (2002). In someembodiments, the patient in need of treatment by the methods of theinvention is in need of beta blockade and is either undergoing aprocedure under spinal anesthesia or was administered spinal anesthesiawithin the last 36 hours.

In a study analyzing the potential of bisoprolol (a beta blocker) as anagent to protect patients at risk for cardiovascular complicationsundergoing surgery with spinal block, researchers identified apolymorphism in the ADRB2 gene as a predictor of hypotension. See Zaugg,Anesthesiology, 107:33-44 (2007). Zaugg et al. found that individualswith the Gly16Arg polymorphism (refSNP ID: rs1042713; SEQ ID NO: 1) weremore likely to experience hypotension following administration ofbisoprolol. Thus, in some embodiments, the patient in need of treatmentby the methods of the invention is in need of beta blockade and carriesthe ADRB2 Gly16Arg polymorphism.

Additionally, it is known that patients of Asian ancestry are moresusceptible to esmolol-induced hypotension. See Ko et al., JACC 23:302-6(1994). Using the manufacturer-recommended loading infusion of 500 μg/kgbody weight per minute, Ko et al. found that all patients administeredthis dosage experienced acute hypotension. Id. at 303. Only by loweringthe loading dose and maintenance dose were the researchers able tocontrol supraventricular tacharrhythmia without causing hypotension. Id.at 302. Thus, in some embodiments, the patient in need of treatment bythe methods of the invention is in need of beta blockade and is of Asianancestry, for example, the patient can be of Chinese ancestry.

EXAMPLES

The following examples are provided for illustration and are not in anyway to limit the scope of the invention.

Table 1 lists properties of the esmolol composition utilized in thefollowing studies. “Batch number” refers to the intended concentrationof esmolol hydrochloride. “Actual Esmolol concentration” refers to theactual concentration of esmolol hydrochloride in each particularformulation as determined by a non-chiral HPLC method at the time theformulation was prepared (“pre-animal testing”) or after animal testing(“post-animal testing”) as indicated below. A chiral HPLC method wasused to determine the ratio of S-isomer to R-isomer in the compositions.The actual esmolol concentrations determined pre-animal testing wereused to determine animal dosing. The small concentration variancebetween pre-animal testing and post-animal testing values demonstratesthe stability of the compositions. The pH of each formulation wasdetermined pre-animal testing and post-animal testing. Osmolality wasdetermined post-animal testing.

TABLE 1 Composition Actual Actual Esmolol Esmolol Testing concentrationconcentration Ratio pH pH Batch (pre-animal (post-animal S-isomer:R-Sodium Sodium Acetic (pre-animal (post-animal Osmolality number Isomertesting) testing) isomer Chloride Acetate Acid testing) testing)(mOsm/kg) 10 S-Isomer  8.98  8.97 99.4:0.6 5.9 2.8 0.546 4.91 4.87 304mg/mL mg/mL mg/mL mg/mL mg/mL mg/mL 20 Racemate 20.48 20.52  50:50 4.12.8 0.546 4.88 4.83 299 mg/mL mg/mL mg/mL mg/mL mg/mL mg/mL 25 S-Isomer21.72 21.86 98.5:1.5 3.2 2.8 0.546 4.88 4.81 322 mg/mL mg/mL mg/mL mg/mLmg/mL mg/mL 25 R-Isomer 24.88 25.19  1.6:98.4 3.2 2.8 0.546 4.98 4.91299 mg/mL mg/mL mg/mL mg/mL mg/mL mg/mL

Example 1 Establishment of a Model System to Analyze the Contribution ofEsmolol Enantiomers to Hypotension

A model system utilizing anesthetized mongrel dogs was established inorder to predict the hypotensive potential of esmolol hydrochlorideinjection in human patients. One dog was administered a formulationcontaining racemic esmolol hydrochloride at a loading dose of 600μg/kg/min for 3 minutes followed by a maintenance infusion of 300μg/kg/min for 10 minutes (referred to as 600RS/300RS) followed by awashout period (FIG. 1). In this and subsequent figures, the duration ofinfusion of the various medicaments is indicated by a coded horizontalline, parallel to the time axis. This protocol was repeated byadministering 2000 μg/kg/min for 3 minutes followed by a maintenanceinfusion of 1000 μg/kg/min for 10 minutes (referred to as 2000RS/1000RS)and then by administering 400 μg/kg/min for 3 minutes followed by amaintenance infusion of 200 μg/kg/min for 10 minutes (referred to as400RS/200RS). Mean arterial blood pressure and heart rate were monitoredthroughout the experiment. There was a clear dose-dependent decrease inmean arterial blood pressure in response to administration of theracemic formulation of esmolol hydrochloride, which was accompanied by adose-dependent reflex tachycardia. While esmolol administration isnormally expected to reduce heart rate, similar reflex tachycardia havebeen reported in humans secondary to hypotension at esmolol doses of 500μg/kg/min and higher See Reilly et al., Clin Pharmacol Ther. 38:579-85(1985).

These data indicate that the mongrel dog is a relevant species forevaluating the hypotensive potential of different formulations ofesmolol hydrochloride in part because humans are known to similarlyexhibit hypotension (or a hypotensive response) in response to racemicesmolol hydrochloride treatment. While the doses administered to thedogs in the experiments described herein were larger than typicalclinical doses, the doses were administered in order to increaserepeatability and induce acute hypotension in close to 100% of the dogsby sufficiently increasing the effect level above background noise.Moreover, relative to esmolol administration in humans, the dog modelreplicates within experimental error the same dependence of meanarterial blood pressure versus infusion rate. Therefore, the conclusionsreached at these relatively higher dose levels in dogs are relevant tominimization of adverse effects at lower doses in humans.

Example 2 A Composition Comprising the S-Isomer of Esmolol DemonstratesDecreased Hypotensive Potential Relative to the Racemic Formulation

The animal model of Example 1 allowed comparison of compositionscomprising the S-isomer of esmolol and compositions comprising theracemic mixture of esmolol in a complex biological system. While betablockers are often manufactured and commercialized as the RS racemicmixture, the S-isomer is responsible for all of the beta blockingactivity. See Mehvar and Brocks, J. Pharm Pharmaceut Sci, 482:185-200(2001). Thus, the S-isomer of esmolol is about twice as potent as abeta-adrenergic-blocking agent than an equivalent amount of the racemicmixture. See International Patent Publication No. WO 88/01614. In viewof the foregoing, the experiments described herein illustrateadministration of compositions comprising the racemic mixture of esmololrelative to compositions comprising the S-isomer of esmolol, in whichthe administered amount of S-isomer was half the amount of the racemicmixture. Because the S-isomer possesses substantially all of thetherapeutic potential present in the racemic mixture, compositionscomprising half the amount of the S-isomer were consideredequitherapeutic to compositions comprising a given amount of the racemicmixture of esmolol. In other words, when 600 μg/kg/min of thecomposition comprising racemic esmolol was administered, theequitherapeutic dose/infusion rate of the composition comprisingS-isomer administered for direct comparison was 300 μg/kg/min.

In initial experiments, the hypotensive potential of a compositioncomprising the S-isomer of esmolol hydrochloride was compared to acomposition comprising the racemic formulation. Mean arterial bloodpressure, cardiac output, and systemic vascular resistance weremonitored throughout the experiments. Cardiac output and systemicvascular resistance were evaluated to understand the cause of thehypotension (i.e., decrease in cardiac output and/or decrease insystemic vascular resistance).

Each of four mongrel dogs was administered increasing doses of esmololhydrochloride (FIGS. 2-5). Two dogs (D00028 and DG0029) received 150μg/kg/min of the S-isomer formulation until mean arterial pressurereached a steady state, at which time the animal was immediatelyswitched over to 300 μg/kg/min of the racemic formulation (this protocolis referred to as 150S/300RS in FIGS. 3 a and 4 a). Once a steady statewas reached the infusion was stopped and was followed by a washoutperiod. A similar protocol was repeated in both dogs using 300 μg/kg/minof the S-isomer of esmolol followed by administration of 600 μg/kg/minof the racemic mixture of esmolol (this protocol is 300S/600RS in FIGS.3 b and 4 b). A final protocol involved administration of 1000 μg/kg/minof the S-isomer of esmolol followed by administration of 2000 μg/kg/minof the racemic mixture of esmolol followed by 1000 μg/kg/min of theS-isomer of esmolol (this protocol is referred to as 1000S/2000RS/1000Sin FIGS. 3 c and 4 c).

A similar series of protocols were repeated with the other two dogs(DG0027 and DG0030) except the racemic mixture of esmolol wasadministered before the S-isomer. In other words, 300 μg/kg/min of theracemic mixture of esmolol was administered, followed by administrationof 150 μg/kg/min of the S-isomer of esmolol (this protocol is referredto as 300RS/150S in FIGS. 2 a and 5 a), 600 μg/kg/min of the racemicmixture of esmolol was administered, followed by administration of 300μg/kg/min of the S-isomer of esmolol (this protocol is referred to as600RS/300S in FIGS. 2 b and 5 b), and 2000 μg/kg/min of the racemicmixture of esmolol was administered, followed by administration of 1000μg/kg/min of the S-isomer of esmolol, and then 2000 μg/kg/min of theracemic mixture of esmolol again (this protocol is referred to as2000RS/1000S/2000RS in FIGS. 2 c and 5 c)].

Similar to Example 1, the racemic formulation caused a dose-dependentdecrease in mean arterial pressure in all four dogs regardless ofwhether it was administered before or after administration of theS-isomer. At the high dose infusion protocol, there was an unequivocaldifference in mean arterial blood pressure between the two formulations.Specifically, the S-isomer produced significantly less hypotensionrelative to the racemic formulation. In general, the differentiationbetween the S-isomer and racemic formulations on mean arterial bloodpressure was apparent at the middle infusion protocol in which 300μg/kg/min S-isomer and 600 μg/kg/min of the racemic mixture wereadministered (see FIGS. 2 b and 5 b; FIGS. 3 b and 4 b). Thus,differentiation is apparent at a dose of the racemic mixture which isonly approximately two- to three-fold higher than the most clinicallyrelevant infusion rate (i.e., 200 μg/kg/min of the racemic mixture) inhumans. During the 2000RS/1000S/2000RS administration protocol, meanarterial blood pressure increased during the 1000S phase (see FIG. 2 c).These data indicate that the R-isomer is contributing to the hypotensivepotential of the racemic formulation.

Example 3 Compositions Comprising the S-Isomer of Esmolol ExhibitSimilar Efficacy with Less Hypotension Relative to Racemic Formulations

The purpose of this experiment was to determine if the attenuatedhypotension (as assessed by mean arterial blood pressure end point)observed in Example 2 following administration of the S-isomer wasassociated with reduced efficacy (i.e., ability to controlisoproterenol-induced tachycardia) as compared with the racemicformulations.

One dog was administered a bolus dose of isoproterenol (0.25 μg/kg) toestablish a baseline heart rate response (FIG. 6 a). Isoproterenol is anon-selective 131 adrenergic agonist capable of inducing tachycardia.After a washout period, the racemic formulation (RS) was administered at90 μg/kg/min for 10 minutes immediately followed by an isoproterenolchallenge. After a washout period, the S-isomer formulation (S) wasadministered at 45 μg/kg/min for 10 minutes immediately followed byanother isoproterenol challenge. This protocol was repeated using 150μg/kg/min S-isomer followed by 300 μg/kg/min racemic formulation (FIG. 6b) then 2000 μg/kg/min racemic formulation followed by 1000 μg/kg/minS-isomer (FIG. 6 c). Similar to Example 2, the racemic formulationcaused a greater dose-dependent decrease in mean arterial blood pressurerelative to the S-isomer.

At the high infusion rate, there was a significant difference in themean arterial blood pressure response between the two formulations.Specifically, the S-isomer produced significantly less hypotensionrelative to the racemic formulation. As the infusion rate of esmololincreased, a dose-dependent decrease in heart rate was observedfollowing the isoproterenol challenge. The observed dose-dependentdecrease in heart rate is expected, as the number of available receptorsfor isoproterenol to interact with decreases as the dose of esmololincreases. More importantly, equitherapeutic amounts of the S-isomerconsistently demonstrated the same degree of efficacy in reducingisoproterenol-induced tachycardia as compared with the racemicformulation. In total, this data indicates that the S-isomer exhibitssimilar efficacy (heart rate end point) with less hypotension (meanarterial blood pressure end point) as compared with the racemicformulation over a very broad range of infusion rates.

Example 4 The S-Isomer of Esmolol Produces Significantly LessHypotension as Compared with the Racemic and the R-Isomer Formulations

The hypotensive potential of an R-isomer only formulation of esmololhydrochloride was compared to the S-isomer and racemic formulations.Each of three mongrel dogs was administered all three formulations usinga Latin-square design at each of two infusion rates (FIGS. 7-9). Forexample, animal DG0024 received 300 μg/kg/min of the racemic formulationfor 10 minutes, at which time the animal was immediately switched overto 150 μg/kg/min of the S-isomer formulation for 10 minutes, at whichtime the animal was immediately switched over to 150 μg/kg/min of theR-isomer formulation for 10 minutes (this protocol is referred to as300RS/150S/150R in FIG. 7 a) followed by a washout period. This protocolwas repeated in animal DG0024 using the high infusion rate protocol(i.e., 2000 μg/kg/min of the racemic formulation for 10 minutes, 1000μg/kg/min of the S-isomer for 10 minutes, 2000 μg/kg/min of the racemicformulation for 10 minutes; this protocol is referred to as2000RS/1000S/1000R in FIG. 7 b). The treatment sequence and monitoredparameters for animals DG0032 and DG0033 are depicted in FIGS. 8 a and 8b and FIGS. 9 a and 9 b, respectively.

At the low infusion rate, there were no observed differences in meanarterial blood pressure between the three formulations. This finding isconsistent with the findings from Example 2, indicating thatdifferentiation between the S-isomer and the racemic formulations do notmanifest in dogs until infusion rates are approximately 300 μg/kg/minfor the S-isomer of esmolol and 600 μg/kg/min for the racemic mixture.

At the high dose infusion rate, there was a salient difference in meanarterial blood pressure following the S-isomer formulation as comparedwith the racemic formulation. Specifically, mean arterial blood pressureimproved (or increased) following infusion of the S-isomer formulationrelative to the racemic formulation. This finding is also consistentwith that observed in Example 2, above.

The individual animal data from the high dose infusion protocols ofFIGS. 2-5 and 7-9 were combined and are presented in FIG. 10. The changein mean arterial pressure (MAP) from pre-infusion (i.e., restingbaseline state just prior to beginning a particular infusion) values isdepicted as a percent change calculated as follows: [((value at the endof the infusion-value at the start of infusion)/value at the start ofinfusion)*100]. Based on these data, starting from baseline,administration of the RS racemic mixture decreases MAP by 40%, whileadministration of the S-isomer formulation decreases it by only 13%.Interestingly, the effect of administration of the R-isomer formulationlies between these values, resulting in a 19% decrease. The sum of theeffects of R-isomer and S-isomer formulation administration issubstantially equivalent to the effect of RS administration, which isconsistent with the relative infusion rates of the drugs in theseexperiments: 1000 μg/kg/min R and 1000 μg/kg/min S, and 2000 μg/kg/minRS.

The effect of starting from different initial states upon MAP is shownin FIG. 11. Thus, starting from an initial state where the RS racemicmixture has been administered, MAP actually increases 34% uponadministration of the S-isomer, thereby demonstrating thatadministration of the S-isomer formulation causes recovery from thehypotensive effect induced by administration of the racemic mixture. Onthe other hand, starting from an initial state where the animal has beenadministered the S-isomer formulation, subsequent administration of theRS racemic mixture formulation decreases MAP by 32%, an almostequivalent amount in the reverse direction of the RS to S experiment.

The cardiovascular changes following administration of the R-isomerformulation were qualitatively identical to those following theadministration of the racemic formulation. These data indicate that theR-isomer is contributing to the cardiovascular changes observedfollowing the racemic formulation, including the decrease in meanarterial blood pressure (i.e., hypotension). Taken together, the datafrom Examples 1-4 indicate that the R-isomer appears to contributesignificantly to the hypotension observed with administration of theracemic mixture with no apparent, inherent ability to lower heart ratewhen experimentally increased.

Example 5 Compositions Comprising the S-Isomer of Esmolol ProduceSignificantly Less Hypotension and Exhibit Similar Efficacy as Comparedwith Compositions Comprising the Racemic Mixture

The purpose of this experiment was to confirm the results of Example 3demonstrating that the attenuated hypotension (as demonstrated by meanarterial blood pressure end point) following administration of theS-isomer is associated with substantially equivalent efficacy (i.e.,ability to control isoproterenol-induced tachycardia) as compared withthe racemic formulations by testing a broader range of doses and usingan increased number of test subjects than in Example 3.

The experimental protocol was carried out essentially as described inExample 3. In short, each dog was administered racemic esmolol (RS) atthe indicated dose for 10 minutes immediately followed by anisoproterenol challenge (a bolus dose of isoproterenol at 0.25 μg/kg).After a washout period, the S-isomer formulation (S) was administered atan equitherapeutic dose for 10 minutes immediately followed by anotherisoproterenol challenge. This protocol was performed at 90 μg/kg/minRS/45 μg/kg/min S (5 dogs), 300 μg/kg/min RS/150 μg/kg/min S (1 dog),600 μg/kg/min RS/300 μg/kg/min S (3 dogs), 1000 μg/kg/min RS/500μg/kg/min S (4 dogs), and 2000 μg/kg/min RS/1000 μg/kg/min S (3 dogs).

FIG. 12A compares the effects on mean arterial blood pressure and heartrate following isoproterenol challenge in dogs receiving infusions ofracemic esmolol or the S-isomer at the stated infusion rates. Thepercent reduction in heart rate was essentially identical when a givendose of racemic esmolol was compared to an equitherapeutic dose of theS-isomer (i.e., a dose of the S-isomer comprising half the amount of theracemic mixture e.g., 90 μg/kg/min racemic esmolol compared to 45μg/kg/min S-isomer formulation) at all doses. Thus, an S-isomer esmololformulation administered at half the dose of the racemic formulation isable to produce equivalent therapeutic efficacy (i.e., heart ratereduction). However, the hypotensive effect as determined by thereduction in mean arterial pressure differed significantly at dosesgreater than 600 μg/kg/min racemic esmolol/300 μg/kg/min S-isomerformulation. For example, the reduction in mean arterial pressure at aninfusion rate of 1000 μg/kg/min racemic esmolol was about 20 mmHg whilethe reduction in mean arterial pressure was about 10 mmHg at anequitherapeutic dose of 500 μg/kg/min of the S-isomer. Thus, thepresence of the R isomer in the racemic mixture contributessignificantly to the hypotension associated with racemic esmolol.Notably, equitherapeutic doses of the S-isomer consistently demonstratedthe same degree of efficacy in reducing isoproterenol-inducedtachycardia as compared with the racemic formulation (across all doses).

In order to better estimate the true differential effect in hypotensivepotential between racemic esmolol and the S-isomer of esmolol at thelower dose range, data from other dogs that were not part of theisoproterenol challenge experiments, but were otherwise treatedidentically, were combined with the data set from FIG. 12A and presentedin FIG. 12B. The additional data points were only from those dogs wherea stated dose was administered first or where a sufficient wash-outperiod preceded the stated dose as to avoid any confounding variables.Increasing the sample size revealed a statistically significantdifference in mean arterial pressure at the 600 μg/kg/min racemicesmolol (7 dogs)/300 μg/kg/min S-isomer (5 dogs) dose comparison. Thus,the lack of significant differentiation in mean arterial pressure seenat the lower doses in FIG. 12A was likely due to the relatively smallersample size and biological variability.

These data demonstrate that an equitherapeutic dose of the S-isomer ofesmolol can achieve all of the therapeutic efficacy (i.e., heart ratereduction) of a corresponding dose of racemic esmolol with significantlyless hypotension as demonstrated by the respective mean arterial bloodpressure changes over a very broad range of infusion rates.

Example 6 The Relevance of the Dog Model to Humans

The esmolol doses administered to the dogs in the experiments describedherein needed to be larger than typical clinical doses used in humans inorder to increase repeatability and induce acute hypotension in close to100% of the dogs by sufficiently increasing the effect level abovebackground noise. To confirm that the results obtained herein withmongrel dogs are clinically relevant, data from the experimental resultsobtained herein were superimposed with the maximal weighted meandifference in systolic blood pressure results obtained by Yu et al. in ameta-analysis of randomized controlled clinical trials with esmololhydrochloride (Yu et al., Anesth Analg. 2011 February; 112(2):267-81).As is shown in FIG. 13, these data demonstrate that human patientsexperienced clinical hypotension more than two times as severe as thedog model at a given dose of the racemic mixture of esmolol. Furtherstill, FIGS. 12A and 12B demonstrate that significant differentiationwas observed in dogs at a dose of the racemic mixture (i.e., 300μg/kg/min of the racemic mixture) which is clinically relevant inhumans. In view of the greater than two-fold increase in hypotensiveeffect experienced by humans at a given dose of the racemic mixture ofesmolol (relative to an equitherapeutic dose of the S-isomerformulation), these data confirm that the conclusions reached in dogsare relevant to the minimization of adverse effects at even lowerclinically relevant doses in humans.

1. A method for treating tachycardia in a subject, the methodcomprising: administering to the subject a therapeutically effectiveamount of a pharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof, wherein the pharmaceuticalcomposition is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof, and the subject is in needof treatment for tachycardia with control of associated hypotension. 2.A method for treating tachycardia in a subject in need thereof, themethod comprising: administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof, wherein the pharmaceuticalcomposition is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt, and wherein the therapeuticallyeffective amount is administered at a hypotension controlling amountgreater than or equal to 0.3 μmol/kg/min.
 3. The method of claim 1,wherein the therapeutically effective amount comprises a hypotensioncontrolling amount of(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof.
 4. The method of claim 1,wherein the hypotension controlling amount of(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof is greater than or equal to37.5 nmol/kg/min.
 5. The method of claim 1, wherein a therapeuticallyequivalent concentration of a pharmaceutical composition comprising(R,S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionatehydrochloride is likely to cause the subject to develop hypotension. 6.The method of claim 5, wherein a dose corresponding to greater than orequal to 25 μg/kg/min of racemic esmolol hydrochloride is indicated. 7.The method of claim 1, wherein the patient has a condition characterizedby susceptibility to hypotension.
 8. The method of claim 7, wherein thecondition characterized by susceptibility to hypotension is selectedfrom the group consisting of aldosterone deficiency, Ulick syndrome,Visser syndrome, Algrove syndrome, tetrahydrobiopterin deficiency,aromatic L-amino acid decarboxylase deficiency, monoamine oxidasedeficiency, dopamine-β-hydroxylase deficiency, Biaggioni syndrome,Menkes syndrome, familial dysautonomia, hereditary sensory and motorneuropathies, familial amyloidosis, familial olivopontocerebellaratrophy, mitral valve prolapsed syndrome, hereditary mast cellactivation disorder, Bartter syndrome, orthostatic hypotension, familialorthostatic hypotensive disorder, type 1 diabetes, type 2 diabetes, andhypovolemia.
 9. The method of claim 1, wherein the patient has apolymorphism in the ADRB2 gene.
 10. The method of claim 9 wherein thepolymorphism is Gly16Arg (rs1042713; SEQ ID NO: 1).
 11. The method ofclaim 1, wherein the patient is age 65 or older.
 12. The method of claim1, wherein the patient is of Asian ancestry.
 13. The method of claim 12,wherein the patient is of Chinese ancestry.
 14. The method of claim 1,wherein the patient is undergoing a procedure under spinal anesthesia orwas administered spinal anesthesia within the last 36 hours.
 15. Themethod of claim 1, wherein the patient is undergoing a procedure undergeneral anesthesia or was administered general anesthesia within thelast 36 hours.
 16. The method of claim 1, wherein the pharmaceuticalcomposition contains less than 10% by weight(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof based on the total amount ofmethyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof in the composition.
 17. Acomposition for treating tachycardia in a subject in need of treatmentfor tachycardia with control of associated hypotension, wherein thecomposition comprises a therapeutically effective amount of(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof, and is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof.
 18. A composition accordingto claim 17, comprising a hypotension controlling amount of(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof. 19.-30. (canceled)
 31. Acomposition of claim 17, which contains less than 10% by weight(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof based on the total amount ofmethyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof in the composition. 32.-46.(canceled)
 47. A method for controlling heart rate in a subject, themethod comprising: administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate orpharmaceutically acceptable salt thereof, wherein the pharmaceuticalcomposition is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof, and the subject is in needof heart rate control with control of associated hypotension.
 48. Amethod for controlling heart rate in a subject in need thereof, themethod comprising: administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition comprising(S)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt thereof, wherein the pharmaceuticalcomposition is substantially free of(R)-methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate ora pharmaceutically acceptable salt, and wherein the therapeuticallyeffective amount is administered at a hypotension controlling amountgreater than or equal to 0.3 μmol/kg/min. 49.-92. (canceled)